Clinicopathologic and Molecular Subtyping of EGFR Mutation—Response
Authors: Hyun Ae Jung, Jinyeong Lim, Yoon-La Choi, Jhingook Kim, Keunchil Park
Journal: Clinical Cancer Research (2023)

We appreciate the comments from S. Sorscher regarding our recently published article, “Clinical, Pathologic, and Molecular Prognostic Factors in Patients with Early-Stage EGFR-Mutant NSCLC” (1).As noted, our study performed comprehensive analysis of clinical, pathologic, and molecular prognostic factors in patients with early-stage EGFR-mutant non–small cell lung cancer (NSCLC). In this study, TP53 mutation was the most frequently comutated gene (48%). The TP53 mutation group showed inferior recurrent-free survival (RFS) with HR of 2.5. In multivariate analysis, molecular risk factors [non-TRU (terminal respiratory unit) subtype and TP53 mutation] were associated with poor RFS independent of pathologic stage and clinicopathologic risk factors (micropapillary subtype, vascular invasion, and pleural invasion). Several studies revealed that TP53 coalterations as a negative prognostic marker in EGFR-mutant NSCLC and a predictor of worse clinical outcome following EGFR-TKI (tyrosine kinase inhibitor) therapy (2, 3).Li Fraumeni syndrome (LFS) may be as frequent as one in 5,000–20,000 individuals (4). Owing to the rarity of LFS, few case reports of Korean patients have been published (5). In fact, we have also assessed germline testing for TP53 mutations in 56 patients with matched case controls (pathologic stage and the type of EGFR mutation) to rule out the possibility of LFS in our cohort. We used the same normal bam file we used in the article to call the germline variant. Following the GATK best practice pipeline guidelines for germline variant calling, we called all the variants using GATK's Haplotypecaller and annotated using ANNOVAR. As a result, there were no important germline mutations, including TP53, in our cohort. There was no patient who did not meet the Chompret criteria for clinical diagnosis of LFS, either (6). Therefore, LFS is not related to our finding that the somatic co-occurrence mutation of EGFR and TP53 is predicted to be poor RFS.Through our work, we suggested risk stratification treatment strategy in early-stage EGFR-mutant NSCLC. The recent survival curves of ADAURA study appear to show the first converge sign of a waning effect after 3-year osimertinib treatment (7). The high-risk group with EGFR/TP53 mutation might achieve better outcomes with aggressive strategies, including EGFR-TKIs with or without other treatments, such as antiangiogenic agents, chemotherapy, or others. A recent study of apatinib plus gefitinib showed a progression-free survival benefit in patients with TP53 exon 8 mutation (8).By comparing the genomic landscape of lung cancer from Asian and Western countries, they found strong differences in driver mutation, copy-number alteration, RNA transcriptomic subtype, and mutation signatures (9, 10). Therefore, further studies on ethnic differences are also needed.We appreciate the interest in our work and look forward to future studies.See the original Letter to the Editor, p. 686K. Park reports personal fees from AstraZeneca outside the submitted work. No disclosures were reported by the other authors.